The present invention relates to a quinoline-N-oxide derivative having a lipoxygenase-inhibiting action and a pharmaceutical composition containing the same.
Lipoxygenase (1. 13. 11. 12) is an enzyme existing in blood platelets, leukocytes, lymphocytes, etc., and converts polyvalent unsaturated fatty acid (particularly arachidonic acid) to hydroperoxy acid. It is known that positions of hydroperoxy group(s) introduced in arachidonic acid by lipoxygenase are 5th, 8th, 9th, 11th, 12th and 15th positions. For example, it has been reported that lipoxygenase existing mostly in blood platelets, etc. is an enzyme that hydroperoxidizes the 12th position of arachidonic acid (12-lipoxygenase), and there are 5-lipoxygenase and 15-lipoxygenase in leukocytes. Hydroperoxyeicosatetraenoic acid formed from arachidonic acid by lipoxygenase is unstable and is converted to hydroxyeicosatetraenoic acid. These fatty acids formed by lipoxygenase stimulate by themselves physiological actions such as migration of leukocytes and smooth muscles of aortic tunica media, etc., and it has been recently clarified that they are further metabolized in vivo to produce metabolic products having various physiological actions. For example, chemical structure and biosynthesis route of a slow reacting substance of anaphylaxis (abbreviated as SRS-A, which includes leukotriene C, D, E and F) which is formed in lungs of guinea pigs at anaphylaxis or human lungs at asthmatic attacks and has a force to slowly but strongly contract the smooth muscles of bronchus and which has long been regarded as a substance to cause asthma have been recently clarified by Samuelson et al. [Proc. Natl. Acad. Sci. U.S., 77, 2014 (1980)], and it has been found that it is formed by metabolism from arachidonic acid by aid of 5-lipoxygenase. It has been reported that various peroxy lipids such as hydroperoxyeicosatetraenoic acid, hydroxyeicosatetraenoic acid, leucotriene B, SRS-A, etc. which are formed by metabolism by aid of lipoxygenase, are chemical mediators that contract various smooth muscles, for example, smooth muscles of respiratory system (trachea, bronchus, pulmonary tissue), vascular system, digestive organ, accelerate capillary permeability, stimulate migration of leukocytes and smooth muscles of aortic tunica media, and as the result cause bronchial asthma, allergic diseases (atopic dermatitis, inflammation of organs, etc.), diseases of circulatory organs (edema, ischemic heart disease, hypertension, ischemic brain disturbance, arteriosclerosis, etc.) or cause inflammatory diseases.
However, studies of effective compounds on the diseases caused by the lipoxygenase metabolites have not been advanced yet.
As a result of searching preventive and healing agents for the diseases caused by the lipoxygenase metabolites, it has been found that quinoline-N-oxide derivatives are useful as preventive and healing agents, for the diseases caused by the lipoxygenase metabolites.